A Phase 4, Double-Blind, Randomized, Placebo-controlled, Multi- Center Study to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Men with Overactive Bladder (OAB) Symptoms While Taking the Alpha Blocker Tamsulosin Hydrochloride for Lower Urinary Tract Symptoms (LUTS) due to Benign Prostatic Hyperplasia (BPH) PLUS ISN/Protocol 178-MA-1008 ClinicalTrials.gov Identifier: NCT02757768 Date of Protocol Version 5.2: 22 Jan 2018 Sponsor: Astellas Pharma Global Development, Inc. Medical Affairs, Americas 1 Astellas Way Northbrook, IL 60062, USA Sponsor: APGD, Medical Affairs, Americas ISN/Protocol 178-MA-1008 EudraCT 2015-004036-36 - CONFIDENTIAL - A Phase 4, Double-Blind, Randomized, Placebo-controlled, Multi- Center Study to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Men with Overactive Bladder (OAB) Symptoms While Taking the Alpha Blocker Tamsulosin Hydrochloride for Lower Urinary Tract Symptoms (LUTS) due to Benign Prostatic Hyperplasia (BPH) PLUS ISN/Protocol 178-MA-1008 Version 5.2 Incorporating Substantial Amendment 4 [See Attachment 1] 22 January 2018 IND 69,416 EudraCT 2015-004036-36 Sponsor: Astellas Pharma Global Development, Inc. Medical Affairs, Americas 1 Astellas Way Northbrook, IL 60062 Investigator information is on file at Astellas. -------------------------------------------------------------------------------------------------------------------------------------- This confidential document is the property of the Sponsor. No unpublished information contained in this document may be disclosed without prior written approval of the Sponsor. 22 Jan 2018 Astellas Page 1 of 87 Sponsor: APGD, Medical Affairs, Americas ISN/Protocol 178-MA-1008 EudraCT 2015-004036-36 - CONFIDENTIAL - Table of Contents I. SIGNATURES ······················································································ 8 II. CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························10 III. LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················12 IV. SYNOPSIS··························································································17 V. FLOW CHART AND SCHEDULE OF ASSESSMENTS ·································24 1 INTRODUCTION·················································································28 1.1 Background ····················································································28 1.2 Summary of Non-clinical and Clinical Data ···············································29 1.2.1 Mirabegron (YM178) ···································································29 1.2.1.1 Summary of Non-clinical Studies of Mirabegron······························29 1.2.1.2 Summary of the Pharmacokinetics of Mirabegron ····························30 1.2.1.3 Summary of Clinical Data with Mirabegron ···································30 1.2.2 Tamsulosin Hydrochloride ·····························································32 1.2.2.1 Summary of Non-clinical Studies of Tamsulosin Hydrochloride············32 1.2.2.2 Summary of the Pharmacokinetics of Tamsulosin Hydrochloride···········33 1.2.2.3 Summary of Clinical Data with Tamsulosin Hydrochloride··················33 1.3 Summary of Key Safety Information for Study Drugs ···································34 1.3.1 Summary of Key Safety Information for Mirabegron ······························34 1.3.2 Summary of Key Safety Information for Tamsulosin Hydrochloride·············35 1.3.3 Summary of Key Safety Information for Combination of Mirabegron and Tamsulosin Hydrochloride ·····························································35 1.4 Risk-Benefit Assessment·····································································36 2 STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································36 2.1 Study Objectives ··············································································36 2.2 Study Design and Dose Rationale···························································37 2.2.1 Study Design·············································································37 2.2.2 Dose Rationale···········································································38 2.3 Endpoints·······················································································38 2.3.1 Primary Endpoints·······································································38 2.3.2 Secondary Endpoints····································································38 2.3.3 Exploratory Endpoint ···································································39 2.3.4 Safety Variables ·········································································39 22 Jan 2018 Astellas Page 2 of 87 Sponsor: APGD, Medical Affairs, Americas ISN/Protocol 178-MA-1008 EudraCT 2015-004036-36 - CONFIDENTIAL - 3 STUDY POPULATION··········································································39 3.1 Selection of Study Population ·······························································39 3.2 Inclusion Criteria··············································································39 3.3 Exclusion Criteria ·············································································40 4 TREATMENT(S)··················································································42 4.1 Identification of Investigational Product(s) ················································42 4.1.1 Test Drug(s)··············································································42 4.1.2 Concomitant Medication ·······························································43 4.1.3 Placebo····················································································43 4.2 Packaging and Labeling ······································································43 4.3 Study Drug Handling ·········································································43 4.4 Blinding ························································································44 4.4.1 Blinding Method·········································································44 4.4.2 Confirmation of the Indistinguishability of the Study Drugs ······················44 4.4.3 Retention of the Assignment Schedule and Procedures for Treatment Code Breaking ··················································································45 4.4.4 Breaking the Treatment Code for Emergency ·······································45 4.4.5 Breaking the Treatment Code by the Sponsor ·······································45 4.5 Assignment and Allocation ··································································45 5 TREATMENTS AND EVALUATION························································46 5.1 Dosing and Administration of Study Drug(s) and Other Medication(s)················46 5.1.1 Dose/Dose Regimen and Administration Period ····································46 5.1.2 Increase or Reduction in Dose of the Study Drug(s) ································46 5.1.3 Previous and Concomitant Treatment (Medication and Non-Medication Therapy) ··················································································46 5.1.3.1 Previous Medication (Drugs and Therapies) ···································46 5.1.3.2 Concomitant Medication (Drugs and Therapies) ······························47 5.1.4 Treatment Compliance··································································47 5.2 Demographics and Baseline Characteristics ···············································48 5.2.1 Demographics············································································48 5.2.2 Medical History··········································································48 5.2.3 Diagnosis of the Target Disease, Severity, and Duration of Disease··············48 5.3 Efficacy Assessment··········································································48 5.3.1 Patient Diary – Micturition and Incontinence········································48 22 Jan 2018 Astellas Page 3 of 87 Sponsor: APGD, Medical Affairs, Americas ISN/Protocol 178-MA-1008 EudraCT 2015-004036-36 - CONFIDENTIAL - 5.3.2 Patient Perception of Intensity of Urgency Scale (PPIUS) ·························49 5.3.3 Total Urgency and Frequency Score (TUFS) ········································50 5.3.4 International Prostate Symptom Score (IPSS) ·······································50 5.3.5 OAB Symptoms, Quality of Life, Bladder Health and Treatment Benefit ·······50 5.3.5.1 Overactive Bladder-questionnaire (OAB-q)····································50 5.3.5.2 Patient Perception of Bladder Condition (PPBC)······························51 5.3.5.3 EQ-5D-5L ··········································································51 5.3.5.4 Treatment Satisfaction – Visual Analog Scale (TS-VAS) ····················51 5.4 Safety Assessment ············································································51 5.4.1 Vital Signs················································································51 5.4.2 Patient Diary – Subject Measurement Vital Signs···································52 5.4.3 Adverse Events ··········································································53 5.4.3.1 Adverse Events of Possible Hepatic Origin ····································53 1.1.1.1 Adverse Events of Special Interest ··············································53 5.4.4 Laboratory Assessments································································53 5.4.5 Physical Examination ···································································55